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The reactivity of 3-[(dimethylamino)prop-2-enoyl]-4-hydroxyl-1-methylquinolin-2(1H)-one (2) towards different nucleophilic and electrophilic reagents was investigated. The convenient synthesis of several 3-heterocyclyl-quinolinone...
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The reactivity of 3-[(dimethylamino)prop-2-enoyl]-4-hydroxyl-1-methylquinolin-2(1H)-one (2) towards different nucleophilic and electrophilic reagents was investigated. The convenient synthesis of several 3-heterocyclyl-quinolinones such, as 3-pyridazinyl- 10, 11, 3-pyranyl 19a,b and 3-pyrazolylquinolinones 20a,b, 22, 26a,b, 27a,b, 31 and 33 has been described starting from the 3-acetylquinolinone 1 and enaminone 2. In addition, certain heterocyclo[c]quinolinones such as pyrimido- 12, 14 pyrano- 3, 17a,b and pyrazolopyranoquinolinone 29 were obtained in good yields.
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The synthesis of the benzothiophene analogues of the orally active antifungal agents ketoconazole and itraconazole 3a and 3b is reported. The key heterocyclic system 3-(1-piperazinyl)benzo[b]thiophene is prepared by formation of t...
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The synthesis of the benzothiophene analogues of the orally active antifungal agents ketoconazole and itraconazole 3a and 3b is reported. The key heterocyclic system 3-(1-piperazinyl)benzo[b]thiophene is prepared by formation of the enamine between a benzothienone and ethyl 1-piperazinecarboxylate. After elaboration of the respective N-substituents, the methoxy group is cleaved with boron tribromide, and O-alkylated with the corresponding mesylates. [References: 15]
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Nine 2-(pyrazol-1-yl)-4-methylquinolines bearing substituents on the pyrazole 3- or 5-positions (H, Me, Et, i-Pr, t-Bu) were regioselectively synthesized either using the direct condensation of 2-chloro-4-methylquinoline and sodiu...
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Nine 2-(pyrazol-1-yl)-4-methylquinolines bearing substituents on the pyrazole 3- or 5-positions (H, Me, Et, i-Pr, t-Bu) were regioselectively synthesized either using the direct condensation of 2-chloro-4-methylquinoline and sodium salt of 3(5)-substituted pyrazoles or by treatment of 2-hydrazino-4-methylquinoline with an appropriate beta-ketoaldehyde. The H-1 and C-13 chemical shifts were discussed taking into account the preferred conformation about the C-2-N-1' bond as calculated by the AM1 Hamiltonian. It appears that 5-ethyl and 5-isopropyl substituted derivatives present short C-H ... N-1 interactions. Ortho steric effects appear to be responsible for these conformations. [References: 17]
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In solutions of 6(7)-formyl-, 6(7)-acetyl- and 6(7)-p-toluenesulfonyl-2-trifluoromethylperimidines in non-polar solvents, both of the NH tautomers were detected using H-1 NMR spectroscopy even on heating up to 130 degreesC. [References: 12]
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An improved method for the reaction of 2,4-dichlorothiazole-5-carbaldehyde (2) with secondary amines was established using potassium carbonate in acetonitrile at room temperature instead of deprotonation with butyllithium in tetra...
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An improved method for the reaction of 2,4-dichlorothiazole-5-carbaldehyde (2) with secondary amines was established using potassium carbonate in acetonitrile at room temperature instead of deprotonation with butyllithium in tetrahydrofuran at -78 degrees. The method is convenient and the yields of 3 even higher. Compound 2 could also be reacted by this method with thiophenols to yield 4-chloro-2-phenylthiothiazole-5-carbaldehydes 4. [References: 5]
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Conventional risk assessments for crop protection chemicals compare the potential for causing toxicity (hazard identification) to anticipated exposure. New regulatory approaches have been proposed that would exclude exposure asses...
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Conventional risk assessments for crop protection chemicals compare the potential for causing toxicity (hazard identification) to anticipated exposure. New regulatory approaches have been proposed that would exclude exposure assessment and just focus on hazard identification based on endocrine disruption. This review comprises a critical analysis of hazard, focusing on the relative sensitivity of endocrine and non-endocrine endpoints, using a class of crop protection chemicals, the azole fungicides. These were selected because they are widely used on important crops (e. g. grains) and thereby can contact target and non-target plants and enter the food chain of humans and wildlife. Inhibition of lanosterol 14 alpha-demethylase (CYP51) mediates the antifungal effect. Inhibition of other CYPs, such as aromatase (CYP19), can lead to numerous toxicological effects, which are also evident from high dose human exposures to therapeutic azoles. Because of its widespread use and substantial database, epoxiconazole was selected as a representative azole fungicide. Our critical analysis concluded that anticipated human exposure to epoxiconazole would yield a margin of safety of at least three orders of magnitude for reproductive effects observed in laboratory rodent studies that are postulated to be endocrine-driven (i.e. fetal resorptions). The most sensitive ecological species is the aquatic plant Lemna (duckweed), for which the margin of safety is less protective than for human health. For humans and wildlife, endocrine disruption is not the most sensitive endpoint. It is concluded that conventional risk assessment, considering anticipated exposure levels, will be protective of both human and ecological health. Although the toxic mechanisms of other azole compounds may be similar, large differences in potency will require a case-by-case risk assessment
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The increased numbers of patients with compromised immune systems in the last three decades have increased the chances of life-threatening fungal infections. Numerous antifungal drugs have been developed in the last 20 years to tr...
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The increased numbers of patients with compromised immune systems in the last three decades have increased the chances of life-threatening fungal infections. Numerous antifungal drugs have been developed in the last 20 years to treat these infections. The largest group, the azoles, inhibits the synthesis of fungal sterols. The use of these fungistatic azoles has subsequently led to the emergence of acquired azole resistance. The most common mechanisms that result in azole resistance include the overexpression or mutation of the azole target enzyme, and overexpression of drug transporters that are responsible for azole efflux from cells. Additional, less-frequent mechanisms have also been identified. Understanding azole resistance mechanisms is crucial for current antifungal treatment and for the future development of new treatment strategies.
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The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activ...
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The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 mu g/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 mu g/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14 alpha-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 mu g/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae. PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 mu g/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 mu g/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.
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The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activ...
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The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 mu g/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 mu g/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14 alpha-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 mu g/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae. PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 mu g/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 mu g/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.
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Chronic pulmonary aspergillosis (CPA) is a relatively rare, slowly progressive pulmonary syndrome caused by As-pergillus spp. The scarcity of clinical evidence for its management is an important issue. Oral azoles are recommended ...
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Chronic pulmonary aspergillosis (CPA) is a relatively rare, slowly progressive pulmonary syndrome caused by As-pergillus spp. The scarcity of clinical evidence for its management is an important issue. Oral azoles are recommended as the primary treatment of CPA; however, the evidence for their effectiveness is insufficient. Azole-resistant A. fu-migatus is rapidly increasing and becoming a serious concern. Because long-term administration of azoles is the mainstay of CPA, azole resistance may pose a serious threat. Furthermore, prolonged oral administration of azoles may lead to increased azole resistance in CPA patients. Therefore, alternative management strategies for CPA must be considered, and one option may involve the use of intravenous antifungals such as echinocandins and polyens. The utility of these antifungals, however, has not been well evaluated and remains controversial because the drugs are expensive and require patients to be admitted to the hospital for their use. New antifungal drugs with novel mechanisms of action are also needed.
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